Bacterial enoyl-acyl carrier protein (ACP) reductases (FabI and FabK) catalyze the final step in each cycle of fatty acid biosynthesis and are attractive targets for the development of new antibacterial agents. Here, we report the development of novel phenylimidazole derivatives as potent FabK inhibitors with antibacterial activity against
Streptococcus pneumoniae. A representative compound, 1-{[4-(4-bromophenyl)-1
H-imidazol-2-yl]methyl}-3-[5-(pyridin-2-ylthio)thiazol-2-yl]urea (
53) showed strong FabK-inhibitory activity (
S.
pneumoniae FabK IC
50 0.0024µM) and potent
in vitro antibacterial activity against
S. pneumoniae (MIC 0.25 µg/mL). MIC
50 and MIC
90 of compound
53 against 29 clinical isolates of
S. pneumoniae, including penicillin-resistant strains, were 1 and 4µg/mL, respectively. Since an elevated MIC value was observed with a
S. pneumoniae mutant possessing an amino acid substitution in FabK, the antibacterial activity of the compound was considered to be due to the inhibition of FabK. Moreover, this compound showed no significant cytotoxicity. These results suggest that compound
53 is a candidate for anti-pneumococcal agent.
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